<scp>CD19</scp>‐negative relapse in adult patients with relapsed/refractory B‐cell precursor acute lymphoblastic leukemia following treatment with blinatumomab‐a post hoc analysis
Authors: Heinz‐August Horst, Gerhard Zugmaier, Giovanni Martinelli, Noemi Mergen, Kelly Velasco, Faraz Zaman, Hagop Kantarjian
Journal: American Journal of Hematology (2023)

CD19 is expressed on B-cells and is a therapeutic target for patients with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Blinatumomab is a CD3/CD19-directed BiTE® (bispecific T-cell engager) molecule that redirects CD3-positive T-cells to engage and lyse CD19-expressing B-cells. The randomized, multicenter, phase 3 TOWER study (NCT02013167) enrolled 405 patients with Philadelphia chromosome (Ph)–negative relapsed/refractory (R/R) BCP-ALL (blinatumomab n = 271, chemotherapy n = 134).1 Patients treated with blinatumomab demonstrated a significantly longer overall survival (OS; median OS, blinatumomab vs. chemotherapy, 7.7 months vs. 4.0 months; hazard ratio for death with blinatumomab vs. chemotherapy, 0.71; 95% confidence interval [CI], 0.55–0.93; p = 0.01) and a higher rate of event-free survival (EFS; 6-month estimates, blinatumomab vs. chemotherapy, 31.0%, vs. 12.0%; hazard ratio for an event of relapse after achieving a complete remission with full, partial, or incomplete hematologic recovery [CR/CRh/CRi], or death, 0.55; 95% CI, 0.43 to 0.71; p < 0.001) compared with those treated with chemotherapy. The phase 2, open-label, single-arm, multicenter ALCANTARA study (NCT02000427) evaluated the efficacy and safety of blinatumomab in adults with Ph–positive R/R BCP-ALL.2 In this study, 45 patients with disease progression after treatment with ≥1 second or later-generation tyrosine kinase inhibitor (TKI) or intolerant to second or later-generation TKI, and intolerant or refractory to imatinib received two cycles of blinatumomab. The median relapse-free survival was 6.7 months, and the median OS was 7.1 months. Although most patients respond to blinatumomab, a subset of patients with R/R BCP-ALL relapse with loss of expression of CD19 on leukemic blasts. The objective of this retrospective post hoc analysis was to summarize the rate of CD19-negative relapse in adult patients with R/R BCP-ALL following treatment with blinatumomab from the two pivotal trials, TOWER and ALCANTARA, respectively. Detailed descriptions of the study design and patient eligibility for the TOWER and ALCANTARA studies and definition for CR/CRh/CRi have been previously reported.1, 2 All patients enrolled in the TOWER and ALCANTARA studies expressed CD19 at baseline. Patients with disease relapse following treatment with blinatumomab from the TOWER and ALCANTARA studies were identified based on the assessment by the local investigators. Of these patients, those with >5% leukemic blasts in the bone marrow were considered for this analysis. These patients were assessed for CD19 expression using immunocytochemistry analysis (Data S1) based on which they were categorized as CD19-negative or CD19-positive. CD19-negativity was defined as the absence of any detectable CD19 on BCP-ALL blasts. The rate of CD19-negative or CD19-positive relapse was calculated as a percentage of the number of patients who achieved CR/CRh/CRi. Patients with refractory disease were defined as those with progressive disease, non-response to blinatumomab, or partial response upon treatment with blinatumomab and were categorized as CD19-negative or CD19-positive. Time to hematologic relapse was defined as the time from CR/CRh/CRi until the detection of relapse (>5% blasts in the bone marrow). EFS was defined as the time from randomization until relapse following CR/CRh/CRi, or death. OS was defined as the time from randomization to death from any cause. An analysis of the cumulative incidence of CD19-negative relapse in patients who achieved CR/CRh/CRi in response to treatment with blinatumomab from the TOWER and ALCANTARA studies with respect to the time to hematologic relapse was performed. Competing events for this analysis were CD19-positive relapse, extramedullary relapse, progressive disease, and death prior to relapse. All patients signed a consent form in accordance with the Declaration of Helsinki; the study was approved by the Institutional Review Boards of the investigation sites. Baseline characteristics of patients from the TOWER and ALCANTARA studies included in this analysis are shown in Supplementary Table 1 and Supplementary Table 2, respectively. In the TOWER study, a total of 271 patients with R/R BCP-ALL received ≥1 cycle of blinatumomab, of which 119 patients achieved CR/CRh/CRi within 12 weeks from initiation of treatment (Table 1). Upon a median follow-up of 8.3 months, the percentage of patients with CD19-negative relapse was 8.4% (10/119). Of the 75 patients who were refractory to treatment with blinatumomab, 6 patients (8.0%) were CD19-negative (Table 1 and Supplementary Table 3). Overall, of the 194 patients who achieved CR/CRh/CRi or had refractory disease, 8.2% of patients were CD19-negative (Table 1). In the ALCANTARA study, 45 patients were enrolled and treated with blinatumomab of which 16 patients achieved CR/CRh (Table 1). Two (12.5%) of these 16 patients experienced a CD19-negative relapse. Of the 18 patients who were refractory to blinatumomab, none of the patients were CD19-negative (Table 1 and Supplementary Table 3). Overall, of the 34 patients who achieved CR/CRh/CRi or had refractory disease, the percentage of patients who were CD19-negative was 5.9% (Table 1). Of the 135 patients who achieved CR/CRh/CRi in response to treatment with blinatumomab from the TOWER and ALCANTARA studies (119 from TOWER and 16 from ALCANTARA), the cumulative incidence of CD19-negative relapse was estimated in 133 patients; 2 patients for whom the status of expression of CD19 was unclear were not included in the analysis (Supplementary Figure 1A). The estimated cumulative incidence of CD19-negative relapse at 3 months and 10 months from CR/CRh/CRi was about 2.0% and 11.0%, respectively. The cumulative incidence of CD19-negative relapse in patients from TOWER and ALCANTARA is shown in Supplementary Figure 1B and Supplementary Figure 1C, respectively. Assessment of CD22, CD79a, and CD10 in patients with CD19-negative relapse from both the TOWER and ALCANTARA studies showed that most patients expressed CD22 (Supplementary Table 4). The status of expression of CD22, CD79a, CD13, and CD10 in patients who were refractory to blinatumomab and were CD19-negative is shown in Supplementary Table 5. The median time to hematologic relapse (124.5 days [range, 47–292]) in patients with CD19-negative relapse from the TOWER study was comparable to that in patients with CD19-positive relapse (median time to hematologic relapse, 143.0 days [range, 45–693]; Supplementary Table 6). The median duration of EFS (187.5 days [range, 78–329]) and median OS (297.0 days [range, 214–587]) in patients with CD19-negative relapse from the TOWER study were similar to the median EFS and OS in patients with CD19-positive relapse (EFS, 171.0 days [range, 86–723]; OS, 253.0 days [range, 141–773]). A meaningful comparison of the time to hematologic relapse, EFS, and OS could not be done for patients with CD19-negative and CD19-positive relapse from the ALCANTARA study due to the small number of patients (Supplementary Table 7). Of the patients who achieved CR/CRh/CRi upon treatment with blinatumomab, 8.4% of the patients from TOWER and 12.5% of the patients from ALCANTARA relapsed with CD19-negative disease. Additionally, 8.0% of patients from TOWER and no patients from ALCANTARA who were refractory to blinatumomab were CD19-negative. The rate of CD19-negative relapse in patients with R/R BCP-ALL (adult and/or pediatric) calculated as the percentage of the number of patients who relapsed following treatment with blinatumomab or CART-19 has been reported to be in the range of 25.0%–30.0% for patients treated with blinatumomab and 16.0%–100.0% for patients treated with CART-19.3 A broad heterogeneity toward the calculation of the rate of CD19-negative relapse in patients treated with anti-CD19 immunotherapy (blinatumomab or CART-19) has been observed in the published literature wherein the rate of CD19-negative relapse has been calculated as a percentage of the number of patients treated4 or the number of patients with treatment failure5 or the number of patients in remission following treatment.6 Consistency in the reporting of the rate of CD19-negative relapse rate is required to optimize the interpretation of the results and for their effective translation to clinical practice. Salvage therapy for patients with R/R BCP-ALL who relapse following salvage treatment with blinatumomab can be a challenge. However, patients with prior exposure to blinatumomab can respond to subsequent treatment with CART-19. Per a recent report regarding the pivotal phase 1/2 ZUMA-3 study, the rate of CR/CRi among patients with R/R BCP-ALL treated with CART-19 with prior exposure to blinatumomab in any line (12 of 21 patients; 57%) was similar to the rate of CR/CRi observed in the overall patient population treated with CART-19 (31 of 45 patients; 69%).7 A recent report based on a retrospective multicenter analysis of 420 patients aged ≤25 years who were treated with CART-19 demonstrated that although prior exposure to blinatumomab led to downregulation of CD19 expression, it did not preclude a response to salvage therapy with CART-19.8 Poor response to prior treatment with blinatumomab, rather than prior exposure to blinatumomab, was therefore predictive of poor outcome to subsequent therapy with CART-19. In addition to the serial monitoring of CD19, identification of additional B-lineage or other specific markers which are consistently expressed on B-cells could aid in effective monitoring of recurrent disease and contribute to treatment strategy. Of the 12 patients with CD19-negative relapse from both the TOWER and ALCANTARA studies assessed in the current analysis, blasts from the majority of patients were positive for the expression of CD22 (11 of 12 patients). Additional studies to confirm these observations would be required. A limitation of this analysis was its post hoc nature and the limited number of patients. In conclusion, the rate of CD19-negative relapse in patients from the TOWER and ALCANTARA studies calculated as the proportion of the number of patients who responded or were refractory to treatment with blinatumomab was low. Additional studies designed to prospectively measure the incidence of CD19-negative relapse in patients with Ph-positive and Ph-negative R/R BCP-ALL treated with blinatumomab are warranted. The authors thank all the site investigators and patients who participated in the study. Swapnil Kher, PhD, of Cactus Life Sciences (part of Cactus Communications) provided medical writing assistance funded by Amgen Inc. Bob Dawson (Cactus Communications, on behalf of Amgen Inc.) provided graphics support. This study was funded by Amgen Inc. Heinz-August Horst reports research funding and travel support from and participation in advisory boards for Amgen; participation in advisory boards for Pfizer, Jazz Pharmaceuticals, and Novartis; and research funding from Regeneron. Gerhard Zugmaier is employed by Amgen, Inc. and owns stocks in Amgen including patent numbers 10 696 744, 20 170 327 581, 9 688 760, 9 486 475, 20 140 228 316, and 20 140 227 272. Giovanni Martinelli has competing interests with Novartis, BMS, Roche, Pfizer, ARIAD, MSD. Noemi Mergen, Kelly Velasco, and Faraz Zaman are employed by Amgen and own stocks in Amgen. Hagop Kantarjian reports research funding from AbbVie, Agios Pharmaceuticals, Amgen, ARIAD, Astex Pharmaceuticals, Bristol-Myers Squibb, Cyclacel Pharmaceuticals, Daiichi-Sankyo, ImmunoGen, Jazz Pharmaceuticals, Novartis, and Pfizer and honoraria from AbbVie, Actinium Pharmaceuticals, Agios Pharmaceuticals, Amgen, ImmunoGen, Orsenix, Pfizer, and Takeda. All patients provided a signed informed consent before the start of any study-related procedure. The studies were conducted in accordance with the International Council for Harmonization Good Clinical Practice Guideline and conformed to the provisions of the Declaration of Helsinki. Qualified researchers may request data from Amgen clinical studies. Complete details are available at the following: http://www.amgen.com/datasharing. Data S1. Supporting information. Supplementary Figure 1A. Cumulative incidence of CD19-negative relapse in patients treated with blinatumomab from the TOWER and ALCANTARA studies who relapsed following achievement of CR/CRh/CRi or CR/CRh, respectively. Supplementary Figure 1B. Cumulative incidence of CD19-negative relapse in patients treated with blinatumomab from TOWER who relapsed following achievement of CR/CRh/CRi. Supplementary Figure 1C. Cumulative incidence of CD19-negative relapse in patients from ALCANTARA who relapsed following achievement of CR/CRh. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.